title: HIV-1 vaccine-induced T-cell responses cluster in epitope hotspots that differ from those induced in natural infection with HIV-1.
abstract: Several recent large clinical trials evaluated HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5) vectors expressing HIV-derived antigens. These vaccines primarily elicited T-cell responses, which are known to be critical for controlling HIV infection. In the current study, we present a meta-analysis of epitope mapping data from 177 participants in three clinical trials that tested two different HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level epitope responses in these trials by generating population-based epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1) Are vaccine-induced responses randomly distributed across vaccine inserts, or do they cluster into immunodominant epitope hotspots? (2) Are the immunodominance patterns observed for these two vaccines in three vaccine trials different from one another? (3) Do vaccine-induced hotspots overlap with epitope hotspots induced by chronic natural infection with HIV-1? (4) Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5) Can epitope prediction methods be used to identify these hotspots? We found that vaccine responses clustered into epitope hotspots in all three vaccine trials and some of these hotspots were not observed in chronic natural infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same vaccine in different populations. Some of the vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5 HIV vaccine. Finally, we found that epitope prediction methods can partially predict the location of vaccine-induced epitope hotspots. Our findings have implications for vaccine design and suggest a framework by which different vaccine candidates can be compared in early phases of evaluation.
authors.affiliation: Statistical Center for HIV Research and Prevention, Vaccine and Infectious Disease Division and the HIV Vaccine Trials Network, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. thertz@fhcrc.org
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: Hasan
authors.initials: H
authors.lastname: Ahmed
authors.forename: David P
authors.initials: DP
authors.lastname: Friedrich
authors.forename: Danilo R
authors.initials: DR
authors.lastname: Casimiro
authors.forename: Steven G
authors.initials: SG
authors.lastname: Self
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.forename: Helen
authors.initials: H
authors.lastname: Horton
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.forename: Peter
authors.initials: P
authors.lastname: Gilbert
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D015331:Cohort Studies; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte